STUDIES ON PATHOLOGY OF BISPHENOL – A TOXICITY IN RATS WITH SPECIAL REFERENCE TO REPRODUCTIVE SYSTEM
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2011-08
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ABSTRACT :
Bisphenol A (BPA) is one of the common environmental endocrine disruptors with estrogenic properties and is the building block of carbonate plastic and a component of resin coatings. Wide spread use of BPA in consumer products has led to great public concern since adverse effects of BPA on human and animal reproduction are suspected due to its estrogenic activity. BPA has high affinity to estrogen related receptor (ERR -) which may be related to its ability to function as endocrine disruptor. Exposure to BPA can induce a number of effects including neuro and hepato toxicity, hematobiochemical effect, endocrinal disturbances, genotoxicity, reproductive toxicity and alters the immune system. The present experiment was designed to make a systematic study of experimentally induced BPA toxicity in both male and female Wistar albino rats at 500 and 250 mg /kg b.wt. to groups II , V and III , VI respectively by mixing in sunflower oil for 12 weeks, with the objectives of finding out the effect of BPA toxicity on hemato- biochemical, oxidative damage, hormonal assay, reproductive toxicity, immunological, genotoxicity, gross and histopathological and ultra structural changes..
Specific clinical signs were not observed, except reddish discoloration of hair was noticed around nose and on back region of BPA treated female rats. Hematologically significant (P<0.05) reduction was recorded in the Hb, PCV and TLC values in toxin fed groups. Blood glucose, and serum total protein values were decreased significantly (P<0.05) in BPA treated rats. Oxidative damage indicators like SOD, catalase and GPx levels were decreased in liver and kidney of all the BPA treated groups. Hormonal assay revealed significant (P<0.05) increase in T3, T4 and E2 levels in BPA fed groups. Immunosupression was indicated by significant (P<0.05) decrease in HA titer (log) and DNCB contact sensitivity score. DNA damage was evident as significant (P<0.05) increase in micronuclei in PCE cells of BPA treated groups when compared to control.
In the present study grossly moderate enlargement of liver with rounded borders with paleness and reduction in size of testis were observed in all BPA treated groups in a dose dependent manner. Enlargement of spleen was observed during 2-4 weeks of the experiment but by the end of experiment, reduction in the size of the spleen was prominent in BPA treated groups. Enlargement of heart was noticed in BPA treated male rats from 6th week onwards and it was more conspicuous by the end of 12th week and this lesion was not more conspicuous in female rats.
Histopathologically, the liver revealed binucleated cells, hyper chromatic nuclei, karyomegaly, focal loss of hepatocytes with moderate MNC infiltration, moderate to severe vesicular fatty change, extensive bile duct proliferation with dysplasia and proliferation of endothelial cells in BPA treated groups in dose dependent manner. Kidney sections of BPA treated rats revealed dose dependent congestion of glomeruli, tubular degeneration, glomerular edema and mesangial cell proliferation.
Submeningeal and cerebral hemorrhages and spongiosis, swollen neurons with severe degenerative changes, extensive glial cell proliferation, severe demyelinating changes, microgranuloma formation with proliferation of capillaries and endothelial cells were more prominent in cerebral cortex of majority of BPA treated groups in a dose dependent manner. Cerebellum of rats revealed shrinkage and focal loss of Purkinje cells, rounding and tapering of Purkinje cells, spongiosis in molecular layer in majority of animals at the end of 10th to 12th weeks in BPA treated groups.
Microscopically, lungs revealed congestion, fatty infiltration, peribronchial lymphoid aggregates and infiltration of eosinophils, vacuolated alveolar epithelial cells, infiltration of alveolar macrophages, hyperplasia of bronchiolar epithelium and focal alveolar epithelial cell proliferation with papillary projections and desquamated bronchial epithelial cells were found as constant lesion by the end of 12th week in a dose dependent manner.
Testis showed interstitial edema, shrinkage of tubules, basement membrane with spermatogonial cells, desquamated seminiferous tubular germ cells, vacuolation in sertoli cells and presence of multinucleated cells in seminiferous tubules were conspicuous by the end of 12 weeks. Hyperplasia of seminal vesicles with papillary projections and prostate carcinoma were noticed in BPA treated rats.
Degenerated follicles, granulosa cell tumor, androblastoma changes were noticed in ovaries of BPA treated rats. Sections of uterus revealed degenerative changes in endometrial glands, infiltration of mono nuclear cells, eosinophils and plasma cells, adenomyosis, dysplasia of endometrial glands and cystic glands by the end of 12th week in majority of BPA treated rats in dose dependent manner. In sections of mammary glands degenerated acini with desquamated epithelial cells in lumen and proliferated acinar epithelial cells were observed in BPA treated rats.
Pancreas revealed degenerated Islets of Langerhans, thickened and hyalinized blood vessels, hyperplasia of ductular epithelium, focal MNC infiltration, necrosis and atrophy of islets, vacuolar degeneration in acinar epithelium and interlobular hemorrhages were more conspicuous in majority of animals in BPA treated groups when compared to control group by the end of 12th week.
Thyroid of BPA treated rats revealed dose dependent changes like hemorrhages, severe desquamation of acinar epithelial cells, complete absence of colloid in acini throughout experimental period and thyroid adenocarcinoma was observed by the end of 12th week.
Degenerative changes in adrenal gland and depletion of lymphocytes in spleen, lymph node and thymus were noticed in all BPA treated rats in dose dependent manner.
Skin of BPA treated groups revealed mild MNC infiltration in dermis, thinning of epidermis, cystic hair follicles and hyperplastic hair follicular epithelium with infiltration of eosinophils in dose dependent manner.
Histochemically more intense alkaline phosphatase reaction was noticed in hepatocytes around central vein, in tubular epithelium and basement membrane of proximal convoluted tubules of kidney and spermatogonia of seminiferous tubules of BPA fed groups in dose dependent manner.
Immunohistochemically increased expression of VEGF was observed in hepatocytes around central vein, in the lining epithelium of oviduct and endometrial glands of BPA treated rats in dose dependent manner. Increased expression of Bcl2 was observed in endometrial glands of BPA treated rats.
Ultra structurally, hepatocytes of BPA treated groups revealed decreased mitochondria with degeneration, fragmented endoplasmic reticulum, and clumping of nuclear chromatin. Where as kidneys revealed loss of brush border, flattened nucleus, degenerated mitochondria and chemical deposition. Granular mitochondria because of degeneration of cristae, degeneration of ER, vacuolation in cytoplasm and fragmented chromatin in astrocytes and numerous vacuoles in cytoplasm with disrupted nuclear membrane and condensation of chromatin in microglial cells were noticed in brain of BPA treated rats. Electron microscopic examination of sertoli cells revealed decreased number of cell organelles and few mitochondria in cytoplasm and disrupted nuclear membrane in all BPA treated male rats in dose dependent manner.